Currently, clinically available NMDA receptor antagonists include ketamine, dextromethorphan, amantadine, and memantine. They bind to the channel site and are considered relatively low-affinity agents. The opioid analgesic methadone is also known to express NMDA receptor antagonistic properties. Unfortunately, direct competitive NMDA receptor blockers that bind to the site of glutamate (e.g., AP5), as well as high-affinity noncompetitive antagonists, all exhibit inadequate therapeutic margins for human use when evaluated in clinical trials [11–15].

The antagonism of NMDA activity and subsequent inhibition of central sensitization offers a valuable pain treatment approach. NMDA antagonists can be efficacious in the treatment of chronic pain states, particularly neuropathic pain, as well as in the management of any non-neuropathic opioid-resistant pain due to developing opioid tolerance or opioid-induced hyperalgesia (OIH). Apparent opioid-sparing effects of these drugs also make them an attractive therapy in the acute pain setting.

In patients with chronic pain states that have been refractory to more standard therapy, particularly neuropathic pain, NMDA receptor antagonists have been frequently utilized. Studies evaluating high-dose IV ketamine in the treatment of complex regional pain syndrome (CRPS) have demonstrated substantial decreases in pain scores and, in some instances, complete resolution of study subjects’ pain [16, 17]. There is also some evidence that the use of ketamine at sub-anesthetic doses also improves a multitude of pain parameters in patients with CRPS [15, 18–20]. One particular case series of six patients with CRPS who underwent treatment with the NMDA receptor antagonist memantine for 6 months demonstrated improved pain scores and other markers of disease, including functional MRI changes [21].

In postherpetic neuralgia that has been refractory to more conventional treatment, intravenous ketamine has shown to be an effective therapy in decreasing initial visual analogue scale (VAS) pain scores and offering sustained pain relief 1 year following initial treatment [22]. Several studies have focused upon the use of ketamine in the treatment of phantom limb pain. One such study demonstrated ketamine to be superior to calcitonin in the treatment of persistent phantom limb pain [23]. Yet another study evaluating epidurally administered ketamine with local anesthetic demonstrated improved short-term analgesia and decreased mechanical sensitivity in patients suffering from phantom limb pain condition, further substantiating the role of NMDA receptor antagonism and its inhibition of central sensitization [24]. Memantine has also been evaluated for the treatment of phantom limb pain. While some findings were inconclusive, the overall trend suggests that memantine may serve as a useful adjuvant agent for this disorder [25–28].

NMDA receptor antagonists may play a particularly important role in cancer-related opioid- resistant pain treatment. Utilization of high doses of opioid analgesics may lead to the development of opioid unresponsiveness in oncology patients. OIH, pharmacodynamic, pharmacokinetic, and learned tolerance can all cause decreased opioid efficacy in this patient population [29]. Many studies published during the last decade showed that low to moderate doses of ketamine significantly improve analgesia in patients with opioid refractory cancer pain [30–34]. In dissonance, one systemic review demonstrated lack of suitable randomized trials and insufficient evidence to make recommendations for routine use of ketamine for cancer pain [35]. The most recent work by Kapural et al. failed to prove the use of ketamine as an effective way to lower long-term pain scores in patients taking high-dose opioids in the settings of neuropathic or nociceptive pain [16].

The role of OIH in clinical situations has been demonstrated in some chronic pain patients, many of who were taking “megadoses” of opioid [36–39]. It has been shown that the addition of an NMDA receptor antagonist for the management of patients who have failed to benefit from opioid rotation or other adjunctive treatments may lead to a more favorable clinical outcome. Several publications report the successful use of ketamine for OIH [40–42]. Methadone, with its D-isomer demonstrating NMDA receptor antagonism, is also mechanistically appealing for the treatment of OIH [43–46]. Dextromethorphan has been studied to assess its clinical utility in treating OIH or limiting tolerance with mixed results [47, 48].

Opioid-sparing effects of NMDA receptor antagonists is well established. The combination of NMDA antagonists with opioid and other non-opioid analgesics can act in synergism, providing an optimal multimodal approach to the management of pain. Ketamine has been demonstrated to provide opioid-sparing effects, facilitate postsurgical rehabilitation, and offer decreased postoperative pain in patients following total hip arthroplasty [49]. Likewise, low-dose ketamine administration has been shown to decrease postoperative morphine consumption and improve postoperative analgesia in patients undergoing major abdominal surgery [50]. Amantadine, most known for its antiviral and antiparkinsonian effects, has been shown to lower the morphine dose requirements and VAS pain scores in patients undergoing radical prostatectomy [51].

A considerable number of clinical studies (both controlled randomized studies and case observations) have been conducted to test the above hypotheses. Clinically available agents, all with the NMDA receptor antagonist properties, were commonly used in these studies. Unlike unequivocal results from the bench studies, however, clinical outcomes of pain relief using NMDA receptor antagonists have varied substantially among different studies.

The role of the NMDA receptor mechanism in persistent pain states is overwhelmingly supported by the data from a large number of preclinical studies, yet outcomes from clinical studies are far less certain. One obvious limitation in assessing the role of the NMDA receptor mechanism in clinical pain management has been the lack of highly selective NMDA receptor antagonists suitable for clinical use.

The concept of preemptive analgesia suggests that postoperative pain intensity could be enhanced due to the process of central sensitization driven by repeated peripheral nociceptive input and mediated through the NMDA receptor. As such, blocking the establishment of central sensitization preoperatively with a clinically available NMDA receptor antagonist would be expected to prevent the development of postoperative pain hypersensitivity. This potentially beneficial effect would be reflected as diminished pain intensity, hence a lower pain score and/or a reduced consumption of analgesics (such as opioids) in surgical patients who receive perioperative treatment with a clinically available NMDA receptor antagonist. To date, nearly all of the clinical studies examining preemptive analgesia have been conducted along this line of experimental design. Several important issues on this topic deserve some discussion.

Side effects of NMDA receptor antagonists when administered at therapeutic doses are a primary limiting factor in their use in clinical practice today (Table 6.2). They may cause psycho-cognitive issues, sedation, respiratory depression, and cardiostimulatory derangements. Alterations in body image and mood, feelings of unreality, floating sensation, hallucinations, restlessness, vivid dreams, dissociation, insomnia, fatigue, delirium, confusion, and drowsiness are among the cognitive adverse effects described in the literature [52]. Increased blood pressure and heart rate are the most common cardiovascular complications [40]. NMDA receptor antagonists were found to trigger a dose-dependent neurotoxic reaction in the cingulated and retrosplenial cortices of adult rats when administered as a short-term treatment [53]. Prolonged continuous infusion of intrathecal ketamine has been associated with spinal cord vacuolization [54]. However, most of the mentioned side effects have been reported with intravenous or subcutaneous administration of this NMDA receptor blocker. Oral ketamine produces few adverse effects [55]. Moreover, the incidence of side effects with ketamine’s systemic use in combination with opioids is low and does not differ from controls treated with opioids only [56]. Specifically, hallucinations occur in 7.4 %, “pleasant dreams” in 18.3 %, nightmares in 4 %, and visual disturbance in 6.2 % of patients [57]. The overall rate of central nervous system adverse effects in patients receiving low-dose ketamine is about 10 % [58]. It is believed that ketamine may cause psychotomimetic effects by disinhibiting certain excitatory transmitter circuits in the human brain [59]. Some drugs such as benzodiazepines can restore the inhibition to this circuitry, providing a neuroprotective effect and reducing the rate of complications [60]. Therefore, concomitant use of benzodiazepines is recommended during ketamine infusion treatment [61]. Another class of medications, alpha-2 adrenergic agonists, may also protect against neurotoxic, psychotomimetic, and cardiostimulatory side effects of NMDA antagonists and, in the case of neuropathic pain, exert a synergistic analgesic effect [18, 62, 63]. Recent studies focusing upon the neramexane and memantine suggest that NMDA antagonists may be used at therapeutic doses without adverse side effects [64, 65].